Itch associated with several conditions can be effectively treated with antihistamines. However itch caused by many conditions, including relatively common dermatological disorders and systemic diseases, can not. These latter types of itch constitute a considerable clinical problem since no effective treatment is currently available. During the previous period of funding, our group has shown that separate populations of primate spinothalamic tract (STT) neurons respond to the itch-producing stimuli intradermal injections of histamine and cowhage, a model of clinically important, non-histaminergic itch. Our results suggest that separate pathways within the CNS carry information regarding histaminergic and non-histaminergic forms of itch. In experiments under Specific Aim 1, we will determine the effects on STT neurons of application of histamine, cowhage, capsaicin, or cathepsin S. These studies will determine whether there are two, or more, distinct pruriceptive pathways within the primate STT. We have also recently found that scratching the receptive fields of STT neurons during a response to histamine inhibited the response for several seconds, mirroring the relief produced by scratching an itchy area of skin. Studies under Specific Aim 2 will determine whether the scratching induced inhibition is dependent solely upon circuitry within the spinal cord or whether there are also important contributions from the brain. Administration of morphine inpatients frequently produces severe itch. This side effect can limit the amount of morphine given to treat chronic pain . Under Specific Aim 3, we will determine whether iontophoretically applied morphine activates pruriceptive and inhibits non- pruriceptive (nociceptive) STT neurons. Our results using antidromic activation techniques revealed that pruriceptive primate STT axons project to several specific nuclei within the posterior thalamus. Under Specific Aim 4, we will record the responses of neurons in these thalamic areas to histamine injections or applications of cowhage. We will identify cortical projection sites of pruriceptive thalamic neurons using antidromic activation. These studies will provide important new information on the processing itch-related information in both the thalamus and cerebral cortex. RELEVANCE (See instructions): The proposed neurophysiological experiments will further our understanding of how itch and pain sensations are mediated by the responses of different types of sensory neurons in the spinal cord and the brain. This will benefit public health by identification of sensory processes in the central nervous system that must be modified pharmacologically in patients suffering from chronic itch or pain.